Social Impact of Alcohol Abuse
Alcohol abuse and alcohol dependence (i.e., alcoholism) are serious public health problems of modem society. In the United States alone, an estimated 13 million adults exhibit symptoms of alcohol dependence due to excessive alcohol intake, and an additional 7 million abuse alcohol without showing symptoms of dependence according to U.S. Government projections. Alcohol dependence and abuse are very expensive: in economic and medical terms, they cost the U.S. well over $200 billion in 1991 with no prospect of falling or leveling off. The social and psychological damages inflicted on individuals as a consequence of alcohol abuse, e.g., children born with fetal alcohol syndrome (FAS) and victims of alcohol-related accidental death, homicide, suicide, etc., are immense.
While it is generally accepted that alcoholism and alcohol abuse are afflictions with staggering international economic, social, medical, and psychological repercussions, success in preventing or otherwise ameliorating the consequences of these problems has been an elusive goal. Only very recently the public view that alcoholism and alcohol abuse are remediable solely by moral imperatives has been changed to include an awareness of alcoholism and alcohol abuse as physiological aberrations whose etiology may be understood and for which therapy may be found through scientific pursuits. Both alcohol abuse and dependence arise as a result of different, complex, and as yet incompletely understood processes. At present, alcohol research is well in the mainstream of scientific efforts.
Pharmacotherapy of Alcohol Abuse
Two important and related goals in pharmacotherapy of alcohol abuse are (1) to reduce alcohol consumption, and (2) to treat co-morbid psychiatric disorders. Essential components of pharmacotherapy include determination of: the optimal therapeutic dose, the minimum effective dose, and the maximum tolerated dose. Latent metabolic effects of chronic, variable-term alcohol abuse, along with intersubject variability must be considered. Therapeutic preparations to reduce alcohol use can be classified as (1) centrally-acting antagonists which prevent or reverse alcohol intoxication without reducing blood alcohol concentration, (2) amethystic agents which directly reduce blood-alcohol concentration, (3) antidipsotropic drugs which associate negative feedback with alcohol drinking, and (4) drugs which tend to attenuate alcohol-craving such as naltrexone, among others.
Antidipsotropic Drugs
The only two pharmaceuticals currently used as alcohol-sensitizing drugs, disulfiram and cyanamide, are both chemically reactive species and non-specific enzyme inhibitors. The alcohol sensitizing drugs disulfiram (tetraethylthiuram disulfide; Antabuse.TM.), and cyanamide in various forms (citrated calcium carbimide; Temposil.TM.) increase blood acetaldehyde concentrations in the presence of ethanol oxidation by inhibiting the oxidation of acetaldehyde to acetic acid, thereby producing physiological effects that deter further alcohol use. The fundamental mechanism for the alcohol-deterrent action of disulfiram and cyanamide is thought to be inhibition of hepatic acetaldehyde dehydrogenase enzymes (ALDH). Drinking alcohol after ALDH inhibition can increase a subject's acetaldehyde concentration by several-fold greater than the acetaldehyde concentration achieved by alcohol-drinking with no ALDH inhibition. Acetaldehyde concentrations so achieved tend to cause intense sickness in the alcohol-drinker. The intense sickness associates negative-feedback with alcohol consumption, thereby conditioning alcohol-drinkers to become alcohol-averse. After decades of testing and use, disulfiram and cyanamide have been demonstrated to have variable toxic effects along with variable effectiveness in causing alcohol aversion
Disulfiram Chemical Properfies
Disulfiram (tetraethylthiuram disulfide) was first proposed as an aversive agent for the treatment of alcoholism by Williams (Williams, 1937, JAMA 109:1472-1473). Williams noticed that workers in the rubber industry who had been exposed to thiuram compounds, used as accelerators of vulcanization, experienced unpleasant effects after alcohol consumption. Disulfiram has been approved for use as a drug since 1948. Disulfiram is a general reagent for determination of SH groups in proteins (Neims et al., 1966, J. Biol. Chem. 241, pp. 3036-3040), and reacts with thiols to form diethylammonium diethyldithiocarbamates, carbon disulfide and disulfide derived from thiol groups (Coffey, supra, pp. 331-332). Disulfiram also undergoes disulfide exchange reactions under mild conditions.
Disulfiram Biological Properties
Given its chemical properties, it is not surprising to find that disulfiram is a broadly acting, non-specific inhibitor of many physiologically important sulfhydryl-containing compounds including enzymes. (Wright and Moore, 1990, Am. J. Medicine, 88:647-655); (for a review, see Banys, 1988, supra). Thus, disulfiram inhibits enzymes critical in neurotransmitter metabolism (dopamine-.beta.-hydroxylase, DBH), drug metabolism and detoxification (microsomal mixed function oxidases), and multiple pathways of intermediary metabolism. It is a potent inhibitor of many liver enzymes, including ALDH, DBH, aniline hydroxylase, nicotinamide-adenine dinucleotide phosphate (NADPH) oxidase, and cytochrome P-450. Other studies have demonstrated inhibition of glyceraldehyde-3-phosphate dehydrogenase, succinic dehydrogenase, xanthine oxidase, hexokinase, and NADPH dehydrogenase. Still other studies have established inhibition of superoxide dismutase, which is thought to be an important antioxidant defense mechanism against free radical-induced biological damage. The details of these and other instances of enzyme inhibition may be found in the references cited in Banys, 1988, supra. Disulfiram's lack of specificity clearly contributes to and may be largely responsible for the substantial toxicity that accompanies the therapeutic use of disulfiram.
In vitro, disulfiram (Pietruszko, 1989, supra) is a potent inhibitor of the high Km cytosolic isozyme (ALDH-II) but inhibits the major acetaldehyde oxidizing mitochondrial isozyme (ALDH-I) only slightly. However, under conditions where trace amounts of certain mercaptans such as 2-mercaptoethanol or the in vivo metabolite methanethiol are added to disulfiram to generate a mixed disulfide, the low Km mitochondrial ALDH-I isozyme, normally resistant to disulfiram, is inactivated. Thus, disulfiram directly inhibits ALDH-II, but only indirectly inhibits ALDH-I via metabolites (Pietruszko, 1989, supra).
In vivo, disulfiram acts slowly to inhibit ALDH over 12 hours, and this inhibition is irreversible (Pietruszko, 1989, supra). Restoration of ALDH activity after disulfiram administration depends upon de novo enzyme synthesis of ALDH, which requires six or more days. Thus, disulfiram and its metabolites have the capacity to shut down hepatic acetaldehyde oxidation via ALDH-I and ALDH-II so that in the presence of ethanol metabolism, abnormally high levels of acetaldehyde will rapidly accumulate. Although exogenous acetaldehyde is known to be toxic, it is not at all clear that endogenous accumulation of acetaldehyde is the only or even the main causative agent in the so-called disulfiram-alcohol reaction (DAR) described below. The direct involvement of acetaldehyde in any of the manifestations of alcohol intolerance is poorly studied, poorly understood and remains unproven.
Disulfiram: Clinical Use and Toxicity
Disulfiram, marketed by Wyeth-Ayerst as Antabuse.TM., is essentially the only alcohol-sensitizing or alcohol-deterrent agent approved for use in the U.S. In a patient metabolizing ethanol, inhibition of ALDH by disulfiram produces the characteristic DAR comprising highly unpleasant physiological reactions including flushing, tachypnoea, palpitations, nausea and tachycardia (Peachey and Naranjo, 1985, Medical Progress, May:45-59). The rationale for treatment with disulfiram is that fear of these reactions will deter alcoholics from further drinking (Peachey and Naranjo, 1985, supra).
As described in the 1996 Physician's Desk Reference (Medical Economics Co., Oradell, N.J., pp. 2358-59), Antabuse.TM., when given to alcohol metabolizing subjects, produces flushing, throbbing in the head and neck, throbbing headache pain, respiratory difficulty, nausea, copious vomiting, sweating, thirst, chest pain, palpitation, dyspnea, hyperventilation, tachycardia, hypotension, syncope, marked uneasiness, weakness, vertigo, blurred vision, and confusion (Physician's Desk Reference, 1991, supra).
Significant cardiac, hepatic, and neurological toxicity, have been observed in patients enduring disulfiram therapy. For example, in severe reactions to Antabuse.TM., there may be respiratory depression, cardiovascular collapse, arrhythmias, myocardial infarction, acute congestive heart failure, unconsciousness, convulsions, and death (see Physician's Desk Reference, supra). These undesirable side effects have been attributed to inhibition of enzymes other than ALDHs, as well as inhibition of the normal physiological functions of one or more of the ALDHs. In fact, many clinicians consider the health risks of disulfiram to be so great, that they refuse to use disulfiram therapy for alcohol abuse. Moreover, many patients either refuse disulfiram therapy or abandon its use. Thus, the art has not yet been provided with a drug for the selective or direct reversible inhibition of ALDH-I without the undesirable side effects or toxicity which accompanies disulfiram treatment.
Placebo-controlled clinical trials of Antabuse.TM. (disulfiram) (Fuller et al., 1986, JAMA 256:1449-1455; Fuller and Roth, 1979, Ann. Int. Med. 90:901-904) have shown that disulfiram is no more effective than placebo controls in reducing alcohol consumption, when compared with pre-treatment levels. According to Banys (Banys, 1988, supra), even though millions of doses of disulfiram have been prescribed for the treatment of alcoholism since 1948, well-controlled studies have never demonstrated that disulfiram is more effective than placebo controls in producing sustained abstinence. Many of the studies published since 1948 suffer from serious flaws. In reviewing the efficacy of disulfiram, Banys (Banys, 1988, supra) supports the contention of Sellers, et al (Sellers et al, 1981, N. Eng. J. Med. 305:1255-1262), that evidence supporting the efficacy of disulfiram is limited. Controlled clinical trials of efficacy show no improvement or short-term improvement only. Appreciable improvements in abstinence and improved social functioning reported by chronic alcoholics during the first three months of treatment with therapeutic (250 mg daily) and sub-therapeutic doses (1 mg daily) of disulfiram, probably result from non-specific, nonpharmacologic drug activity. The subsequent decline from early improvement after the first three months of treatment, probably reflects both the low potency of the drug and the increased importance of non-pharmacologic factors as determinants of long-term outcomes of treatment.
In accord with this, of all the numerous studies of disulfiram, according to Peachey et al (Peachey et al (a), 1989, Brit. J. Addict. 84:877-887), only two properly controlled clinical trials of disulfiram therapy have been conducted, with both concluding that disulfiram was no more effective than placebo controls in bringing about continued, long-term abstinence in alcoholic patients. Thus, the weight of the evidence after more than fifty years of use is that disulfiram is toxic, unsafe and ineffective.
Cyanamide Chemical Properties
The citrated calcium salt of cyanamide resulted from a search for an alcohol-sensitizing agent less toxic than disulfiram (Ferguson, 1956, Canad. M. A. J., 74:793-795; Reilly, 1976, Lancet, Apr. 24, 1976: 911-912), but even now only disulfiram has been approved for use in the United States. Citrated calcium cyanamide is hydrolyzed to free cyanamide (H.sub.2 NCN) in aqueous solution, hence the general properties of cyanamide are relevant. Like disulfiram, cyanamide's alcohol-sensitizing effect was discovered among industrial workers exposed to the substance in the workplace. Although chemically distinct from disulfiram, it is also a reactive species. Cyanamide, which readily forms compounds by addition to the cyano group, yields guanidinium compounds, O-alkylisoureas, and S-alkylisothioureas when reacted with alkyl amines, alcohols and thiols, respectively (Rodd's Chemistry of Carbon Compounds, 1965, Vol. 1, Part C, Coffey, ed., Elsevier, Amsterdam, p.374), (i.e., with nucleophilic functionalities present in proteins). Cyanamide is sufficiently reactive that at slightly alkaline pH it dimerizes to cyanoguanidine, a species that is itself reactive toward nucleophiles (e.g., alkyl amines) (Rodd, 1965, supra, p. 349). Incorporation of citrate in the pharmaceutical formulation provides the slightly acid pH required for stability with respect to dimerization.
Cyanamide Biological Properties
Neither ALDH-I (the low Km isozyme) nor ALDH-II (the high Km isozyme) are inhibited in vitro by cyanamide, but in vivo a reactive product of cyanamide metabolism inhibits both isozymes (Deitrich et al., 1976, Biochem. Pharmacol. 25:2733-2737; DeMaster et al., 1982, Biochem. Biophys. Res. Comm. 107:1333-1339). Formation of this active inhibitor was shown initially to be catalyzed by enzyme(s) present in intact mitochondria and the microsomal fraction of rat liver (DeMaster et al, 1983, Pharmacol. Biochem. Behav. 18 (Supp. 1): 273-277). Mitochondrial catalase has been shown to activate cyanamide to an ALDH inhibitor (DeMaster et al, 1984, Biochem. Biophys. Res. Comm. 122:358-365; Svanas and Weiner, 1985, Biochem. Pharmacol. 34:1197-1204). Further, Shirota et al, (Shirota et al(a), 1987, Alcohol & Alcoholism Supp. 1:219-223 and Shirota et al (b), 1987, Toxicol. Let. 37:7-12), showed that cyanamide inhibits ALDH via a reactive species and that cyanide is generated as a product of cyanamide oxidation by catalase under conditions in which the ALDH inhibitory species is also generated. According to Shirota et al, (Shirota et al.(b), 1987, supra), this cyanide formation could serve as a basis for cyanamide toxicity in vivo. It was postulated in 1987 (Shirota et al.(b), 1987, supra) that the oxidation of cyanamide would yield nitroxyl (HNO) as a product and that this highly reactive species is the active ALDH inhibitor. In 1990, Nagasawa et al (Nagasawa et al, J. Med. Chem. 33:3120-3122) presented evidence, via isotope tracer experiments, that nitroxyl was formed in the catalase-mediated bioactivation of cyanamide. They suggested that their data and those of others support nitroxyl as the active ALDH inhibitor, noting that millimolar concentrations of cyanide do not inhibit ALDH. Marchner and Tottmar (Marchner and Tottmar, 1978, Acta Pharmacol. et Toxicol. 43: 219), reported that inhibition of ALDH with cyanamide is maximal at 1-2 hours after drug administration, and is reversible, with restoration of 80% of the ALDH activity occurring within 24 hours.
Cyanamide: Clinical Use and Toxicity
Absorption of calcium carbimide (i.e. the calcium salt of cyanamide) following oral administration is extremely rapid, causing nausea, headache and vomiting in the presence of ethanol metabolism. In an attempt to reduce the rate of absorption, calcium carbimide has been formulated as a slow release tablet. To prevent its decomposition to ammonia, cyanamide is prepared in the citrated form (one part cyanamide to two parts citric acid). In the gastric environment, calcium carbimide is hydrolyzed to carbimide (cyanamide, H.sub.2 NCN) which is rapidly absorbed into the portal circulation. Data from animal experiments indicate that cyanamide is rapidly absorbed, metabolized and eliminated, and in view of the rapid onset and short duration of the calcium carbimide-ethanol reaction (CER), it is likely that absorption, metabolism and elimination are also rapid in humans. At least 94% of cyanamide is eliminated within six hours via this route by the rat. In Canada and other countries, calcium carbimide has not been widely used because of its short duration of activity. This is due to its facile conversion in vivo to an acetylated derivative, viz. acetylcyanamide (AC), which is rapidly excreted in the urine. Like cyanamide, AC is devoid of ALDH inhibitory activity in vitro.
As with disulfiram, cyanamide has been used in alcohol-aversion and psychological deterrence therapy as described above (Peachey and Naranjo, 1985, supra). Peachey speculated that one reason cyanamide has not yet been approved for use in the United States is because of its suspected antithyroid activity in experimental animals (Peachey, 1981, J. Clin. Psychopharmacol. 1:368-375). However, cyanamide has been used safely for decades in patients with no pre-existing thyroid dysfunction. Citrated calcium cyanamide is marketed variously as Temposil.TM., Dipsan.TM. and Abstem.TM. (Shirota et al.(a), 1987, supra) while Aplain cyanamide, marketed as Colme.TM., is commonly used in Spain (Valerdiz and Vazquez, 1989, Appl. Pathol. 7:344-349).
Cyanamide, like disulfiram is reported to be associated with medical complications. Fewer side effects have been reported with cyanamide than with disulfiram, There are few contraindications to treatment with cyanamide. Toxic effects reported for cyanamide include: (i) allergic contact dermatitis (Conde-Salazar et al., 1981, Contact Dermatitis 7:329-330 and references cited therein), and peripheral neuropathy (Reilly, 1976, supra); (ii) liver injury, including generation of Aground-glass inclusion bodies in liver cells of alcoholics treated with cyanamide (Vazquez et al (a), 1983, Diagnostic Histopath. 6:29-37) first reported by Vazquez and Cervera (Vazquez and Cervera, 1980, Lancet:361-362) using plain cyanamide, and by Thomsen and Reinicke (Thomsen and Reinicke, 1981, Liver 1:67-73) as well as Koyama et al (Koyama et al., 1984, Acta Hepatol. Jpn. 25:251-256) using the citrated calcium salt of cyanamide; a series of reports of hepatotoxicity, including "ground-glass" inclusions, inflammatory reactions associated with liver cell destruction, portal tract fibrosis, scarring, even cirrhosis according to the above-cited references and Vazquez et al (Vazquez et al.(a), 1983, supra; Vazquez et al.(b), 1983, Liver 3:225-230; Bruguera et al., 1986, Arch. Pathol. Lab. Med. 110:906-910; Bruguera et al., 1987, Liver 7:216-222; Valerdiz and Vazquez, 1989, supra), for cyanamide and disulfiram, but not calcium cyanamide; and (iii) cardiotoxic effects, including hypotension and even cardiac death according to Rodger (Rodger, 1962, Br. Med. J. 2:989), and hazardous cardioacceleration according to Kupari et al (Kupari et al., 1982, J. Toxicol.--Clin. Toxicol. 19:79-86); Kupari et al (Kupari et al., 1982, supra) suggested that the use of alcohol aversive drugs including disulfiram and cyanamide has been contraindicated to patients with known cardiac diseases, but pointed out that it is common that asymptomatic chronic alcoholics have a number of cardiac problems. Clearly, use of cyanamide as cited above may be hazardous. However, many of cyanamide's toxic side effects cited above may have been confounded by the presence of elevated blood-acetaldehyde concentrations caused by the cyanamide-ethanol reaction.
Peachey et al (Peachey et al.(b), 1989, Brit. J. Addict. 84:1359-1366), conducted the only placebo-controlled, double-blind clinical trial of Temposil.TM.. Based on this trial, Peachey and his colleagues concluded that this cyanamide was safe for use in alcoholics with normal thyroid function and without other serious medical conditions. Thyroid function was not altered during the Temposil.TM. trial, except for a single patient who entered the trial with sub-normal baseline thyroid function; thus it was concluded that cyanamide was safe for short-term use in alcoholics with without pre-existing thyroid dysfunction. Peachey et al (Peachey et al.(a), 1989, supra), reported that they observed no hepatotoxicity related to cyanamide therapy. The effects of long-term treatment with cyanamide in controlled studies remains unknown.
According to Peachey (Peachey, 1981, supra), in Canada and other countries where cyanamide is approved for safety and efficacy, cyanamide has not been widely used because of its short duration of alcohol-deterrent activity. Peachey et al, (Peachey et al.(a), 1989, supra; Peachey et al.(b), 1989, supra), reported that, compared with pre-treatment levels, cyanamide was no more effective than placebo controls in reducing alcohol consumption. Some reports indicate that use of either disulfiram or cyanamide is counterproductive in treatment of alcoholism. Brien et al (Brien et al., 1980, Eur. J. Clin. Pharmacol. 18:199-205), reported that results from male alcoholic volunteers who ingested small amounts of ethanol after oral administration of cyanamide, supported anecdotal evidence from alcoholics, who state that they can circumvent a severe cyanamide-ethanol reaction by ingesting small amounts of ethanol over a few hours, and thereafter drink excessively with impunity. If cyanamide can be effectively "burned-off" by slow alcohol ingestion for a period followed by excessive consumption, the effectiveness of cyanamide as an anti-alcohol drug appears to be limited.
The variable results of cyanamide's alcohol-deterrent effects as reported above, can likely be explained by considering:
(1) aldehyde dehydrogenase activities within the general population are variable, the precise mechanism by which cyanamide exerts its alcohol-deterrent effects is not well understood, PA1 (2) the severity of the cyanamide-alcohol reaction leads to poor patient compliance with the pharmaco-therapeutic protocol, PA1 (3) cyanamide and related metabolites are water soluble, have a relatively short half-life, and are rapidly cleared via the kidneys.
Thus, it is clear that detecting and measuring cyanamide's alcohol-deterrent-effects can be confounded. However, cyanamide's property of elevating acetaldehyde associated with alcohol-drinking which, in turn results in intense sickness and attenuation of alcohol-drinking, has been demonstrated unequivocally.
The severity of problems caused by alcoholism (alcohol dependence) and alcohol abuse, along with the attendant social and economic costs are immense and well documented and have motivated much research to ameliorate these problems. Numerous pharmacotherapies have been evaluated either as isolated treatment options, or as part of broader support programs (e.g. counseling, Alcoholics Anonymous, etc.).